624 



NATURE 



[August 14, 1913 



phenylarsine acid. The cases of blindness which have 

 been observed after ihe use of very large doses of 

 atoxyl, arsazetin, and other drugs are due to this 

 injury. 



From this it is evident that according to the selec- 

 tion of the group annexed to the phenylarsine acid 

 quite different organs will be affected. This is only 

 explained according to the above views by the fact 

 that there are, as already previously stated, in the 

 various organs specific chemo-receptors which 

 energetically attract certain fixation groups somewhat 

 as the magnet attracts iron. And this view also pro- 

 vides us with the principle according to which we have 

 to construct our poisoned arrows. We must attach 

 to the phenylarsine acid group, or, as the case may 

 be, tn the phenylarsenobenzol group, such grouping as 

 is only related in a small degree to the organs of the 

 sick body, but, on the other hand, is very closely 

 allied to the receptors of the parasites. ■ 



I have explained above that the parasites possess a 

 whole series of chemo-receptors which are specifically 

 different from one another. Now if we can succeed 

 in discovering among them a grouping which has no 

 analogue in the organs of the body, then we should 

 have the possibility of constructing an ideal remedy if 

 we select a haptophoric group which is especially 

 adjusted to the functions of the parasites. 



A remedy provided with such a haptophoric group 

 would be entirely innocuous in itself, as it is not fixed 

 by the organs ; it would, however, strike the parasites 

 with full intensity, and in this sense it would corre- 

 spond to the immune productions, the anti-substances 

 discovered by Behring, which, after the manner 

 of the bewitched balls, fly in search of the enemv. Let 

 us hope that it will be possible chemio-therapeuticallv 

 to hit the bull's-eye in this manner also. I do not 

 consider this at all out of the question, as it may be 

 proved in certain sicknesses, e.g. spirillosis in hens, 

 that from the fiftieth to the hundredth part of the 

 dosis tolerata of salvarsan entirely frees the animals 

 from the "parasites and leads to a cure. Such a dose 

 truly represents a nil dose, as the hen' cannot be 

 damaged thereby in the slightest degree. But such 

 favourable conditions have only very rarely been dis- 

 covered up to the present ; we shall have to be satisfied 

 if we can succeed in obtaining good therapeutic results 

 with the tenth or even the fifth or sixth portion of 

 the dosis tolerata. 



In the main the above are the principles which 

 guided us in the construction of the new remedies. 

 Among the numerous combinations which have been 

 tested in experiments on animals in the case of try- 

 panosomes and spirillar infection, and in the prepara- 

 tion of which I have been supported by the untiring 

 co-operation of Dr. Benda, Dr. Bertheim, Dr. Kahn, 

 and Dr. Karrer, and which have been biologically 

 tested, especially by my respected friend Prof. Hata, j 

 and later by Dr. Castelli and Dr. Gonder and Frl. 

 I.eupold, salvarsan has proved to be the most efficient, 

 the dioxydiamidoarsenobenzol of the formula. 



As = As 



2HN 



NH, 



OH nil 

 Here the orthoamidophenol group acts as the con- 

 ducting and the arsenic group as the toxophoric 

 group. 



But now, gentlemen, the step from the laboratorv 

 to practice, i.e. to the bedside, is an extraordinarily 

 difficult and dangerous one — a step which can onlv 

 be taken with the greatest care. Its difficulty and 

 danger are in the main based upon two factors : — (i) 

 NO. 2285, VOL. 91] 



On the fact that in the case of men there exist so- 

 called idiosyncrasies, forms of supersensitiveness which 

 do not occur in the case of animals ; (2) it has been 

 shown that certain illnesses of a constitutional nature 

 can cause a supersensibility. 



The treatment of patients is an exceedingly difficult 

 and responsible task, and the clinical pioneers, such 

 as Schreiber, Wechselmahn, Iversen, &c, deserve our 

 warmest thanks. They have thrown the first light 

 upon the most important questions (dosologv, indica- 

 tions, and counter-indications). From a series of 

 observations, which is now so vast that it can scarcelv 

 be surveyed, there has, however, resulted what I might 

 call the "therapeutic tactics," which I should here 

 like briefly to explain. 



The therapia sterilisans magna, which consists in 

 this, that by means of one or at most two injections 

 the body is freed from the parasites. In experiments 

 on animals, and also in the case of a series of impor- 

 tant maladies, this principle can be carried through in 

 a clear and pure manner. Here, therefore, the old 

 therapeutic remedy is applicable : " Frapper fort et 

 frapper vite." 



We have to ask ourselves the question, What are 

 the causes which make it possible for a favourable 

 result to be obtained, a result which may be taken as 

 therapia magna sterilisans, radical cure of the bodv 

 by means of a single injection ? Typical antibodies 

 can be shown to be produced fairly rapidly by the 

 destruction of parasites, and especially of protozoa. 

 Hence, it is quite evident that this assisting action of 

 the organism ought to be eminently efficacious. For 

 if the medicine has destroyed not the whole of the 

 parasites, but only 95 per cent., and 5 per cent, have 

 resisted its action, then these remaining 5 per cent, 

 are sure to succumb to the influence of the antibodies 

 which are rapidly formed. If this is the ease, the 

 therapia sterilisans magna is attained. Unfortunately, 

 it has been shown that this salutary process may fre- 

 quently be minimised considerably owing to the 

 biological properties of the parasites. For it may 

 happen that a part of the parasites which survive the 

 first injection escape destruction by the serum either 

 wholly or in part, and subsequently change into new 

 varieties which have become serum-proof, and are 

 known as a relapsing crop. It is clear that parasites 

 of this kind which are able to form a large number 

 of relapsing crops offer very great difficulties in their 

 treatment, as in this case the auxiliary forces of the 

 body fail to act, so that it is necessary to do one's 

 utmost to destroy the whole of the parasites all at once 

 bv means of drugs, as owing to their great power 

 of adaptation a single germ surviving may perhaps 

 be the cause of the infection breaking out afresh. 



If we compare the fight against parasitic diseases 

 with a state of warfare, we find that, on one hand, 

 great battles are fought which may lead to victory 

 in the course of one or a few days. In combating 

 bacteria such a victory would compare with therapia 

 magnq, sterilisata. If, on the other hand, a fortress 

 has to be taken, the goal cannot be reached with one 

 single stroke, but it may take months and even years. 



The measures employed in connection with a bac- 

 teriological siege aim on the whole at rendering the 

 places which are not easily accessible more accessible 

 for the therapeutic agent than is the case under 

 ordinary conditions. On the other hand, however, the 

 greater power of resistance of certain parasites has 

 to be taken into account, and this is a purely chemical 

 question which can only be solved by chemical means. 

 The road leading to its solution which promises the 

 best results is that of combined therapy. 



From what has been said it will be seen that com- 

 bined therapy is best carried out with therapeutic 

 agents which attack entirely different chemo-receptors 



